The proposed Silvio O. Conte Center for Neuroscience of Depression will focus on understanding the neurobiological mechanism of depression. A total of 5 projects are proposed. The center is focused on a single hypothesis. The first project examines localization of lesions, structural changes in critical regions subserving the circuit, alterations in the white matter tracts relevant to the circuit and changes in glutamate. The second project uses post mortem cell counting and cellular localization in serotonin receptors and assessment of the type of cell loss in the orbitofrontal cortex. The third project uses cognitive paradigms and functional MRI to probe the circuit and the role of brain lesions and serotonin on the functioning of this circuit. The fourth project uses transgenic and knockout mice to examine to role of norepinephrine and serotonin as it relates to the circuit. The final project is designed to assess in these transgenic mice using multielectrode array of single neuron recordings of the firing pattern of the circuit neurons in various states and tasks and the role of monoamines in modulating this circuit. Three shared resources, administrative, research and assessment and data management/statistics are proposed to facilitate the conduct of these projects and to ensure integration at the conceptual, analytical and resource availability level, and flow to the various projects. Findings from the center should greatly enhance our understanding of the biology of depressive disorders and help improve the treatment of these disorders. In addition, the technological innovations developed in the context of this project are likely to be of major importance and relevant to other studies of brain function.